Polychlorinated biphenyls (PCBs), and in particular neuroactive non-dioxin-like PCBs, remain a significant children's health concern because of their persistence and inadvertent production by various industrial processes that continue to contaminate food and indoor air, especially in schools across the United States. PCBs have been identified as probable environmental risk factors for neurodevelopmental disorders (NDD), which affect 1 in 10 children born in the United States. Most NDD have complex etiologies that likely involve multiple genetic loci interacting with exposures to environmental factors during critical periods of neurodevelopment. While many genes have been associated with increased risk of NDD, there remains a huge gap in understanding how multiple genes interact to modify neurodevelopment and even less clarity as to how genetic susceptibilities interact with environmental factors to amplify NDD risk. We will address these questions by testing the hypothesis that exposure during critical window(s) of neurodevelopment to a mixture of PCBs found in mothers at risk for having a child with NDD will potently disrupt neuronal connectivity via ryanodine receptor (RyR)-dependent mechanisms and the net outcome will be influenced by heritable mutations that alter the fidelity of Ca2+ signals essential for activity-dependent dendriic growth. This hypothesis derives from data generated during the previous funding cycle demonstrating sensitization of the ryanodine receptor (RyR) by PCB 95 activates calcium-dependent signaling pathways that promote dendritic arborization, and increased dendritic arborization is associated with impaired cognitive behavior in weanling mice exposed to PCB 95 in the maternal diet. The studies described in this application will use a PCB mixture that is relevant to human NDD based on data of PCB levels in the plasma of mothers participating in the MARBLES study at UC Davis, a longitudinal study for pregnant women with increased risk for having a child with NDD. This MARBLES mix will be tested for effects on morphometric, biochemical and functional indices of neuronal connectivity in unique mouse models that express an expansion repeat in the FMR1 gene, the single most frequent monogenetic cause of neurodevelopmental impairments, and a human RyR1 gain of function mutation, singly or in combination. These studies will address the critical need to better understand mechanisms by which non-dioxin-like PCBs cause developmental neurotoxicity, and will provide among the first mechanistic data regarding relevant interactions among genes and environment that increase NDD risk. This information will inform rational strategies for minimizing NDD risk by mitigating relevant exposures and will facilitate the development of mechanistically based screening platforms for identifying other gene-environment interactions likely to amplify adverse neurodevelopmental outcomes.